Imidazo(4,5-b)pyridine-derivatives as inducible no-synthase inhibitors

ABSTRACT

The compounds of formula (I)  
                 
 
in which R 1 , R 2 , R 3 , R 4  and R 11  have the meanings as given in the description are novel effective iNOS inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel imidazo[4,5-b]pyridine derivatives, whichare used in the pharmaceutical industry for the production ofpharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

In the German Patent Application DE 2504252 and in the European PatentApplication EP 0125756 3H-imidazo[4,5-b]pyridine derivatives withanti-ulcer activity are described.

The International Application WO 0049015 describes pyridine compoundswith inhibitory activity on the production of nitric oxide.

DESCRIPTION OF THE INVENTION

It has now been found that the imidazo[4,5-b]pyridine derivatives, whichare described in greater details below, have unanticipated andsophisticated structural features and surprising and particularlyadvantageous properties.

The invention thus relates to compounds of formula I

in which

R1 is hydrogen or 1-4C-alkyl,

R2 is hydrogen, halogen, hydroxyl, nitro, amino, 1-7C-alkyl,trifluoromethyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl,1-4C-alkoxy, completely or predominantly fluorine-substituted1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy,1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminocarbonyl, mono- ordi-1-4C-alkylaminosulfonyl, 1-4C-alkylcarbonylamino,1-4C-alkylsulfonylamino, phenyl, R21- and/or R211-substituted phenyl,phenyl-1-4C-alkyl, phenyl-1-4C-alkyl wherein the phenyl moiety issubstituted by R22, phenyl-1-4C-alkoxy, pyridyl, pyridyl substituted byR23, pyridyl-1-4C-alkyl, pyridyl-1-4C-alkyl wherein the pyridyl moietyis substituted by R24, in which

R21 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl,mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl,amino, mono- or di-1-4C-alkylamino, trifluoromethyl, hydroxyl,phenylsulfonylamino or phenyl-1-4C-alkoxy,

R211 is halogen or 1-4C-alkoxy,

R22 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R23 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R24 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R3 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R4 is 1-4C-alkyl,

R11 is 1-4C-alkyl,

and the salts, the N-oxides and the salts of the N-oxides of thesecompounds.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, and, particularly, the ethyl and methyl radicals.

1-7C-Alkyl is a straight-chain or branched alkyl radical having 1 to 7carbon atoms. Examples are the heptyl, isoheptyl (5-methylhexyl), hexyl,isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl,isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methylradicals.

1-4C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, iso-propoxy, and, particularly, the ethoxy andmethoxy radicals.

3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-Cycloalkyl-1-4C-alkyl stands for one of the abovementioned1-4C-alkyl radicals, which is substituted by one of the abovementioned3-7C-cycloalkyl radicals. 3-7C-Cycloalkyl-1-2C-alkyl, particularly3-7C-cycloalkylmethyl, radicals are to be emphasized in this connection.Examples which may be mentioned are the cyclopropylmethyl, thecyclohexylmethyl and the cyclohexylethyl radicals.

Halogen within the meaning of the present invention is iodine, bromine,chlorine or fluorine.

Completely or predominantly fluorine-substituted 1-4C-alkoxy is, forexample, the 2,2,3,3,3-pentafluoropropoxy, the perfluorcethoxy, the1,2,2-trifluoroethoxy and in particular the

1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical, of which thedifluoromethoxy radical is preferred. “Predominantly” in this connectionmeans that more than half of the hydrogen atoms of the 1-4C-alkoxygroups are replaced by fluorine atoms.

1-4C-Alkoxy-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals which is substituted by the same or another of theabovementioned 1-4C-alkoxy radicals. Examples which may be mentioned arethe 2-(methoxy)ethoxy (-O-CH₂-CH₂-O-CH₃) and the 2-(ethoxy)ethoxyradical (-O-CH₂-CH₂-O-CH₂-CH₃).

1-4C-Alkoxy-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-ethoxyethyl and the3-methoxypropyl radical.

Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the abovementioned 1-4C-alkyl radicals. Preferredare the di-1-4C-alkylamino radicals, especially the dimethylamino, thediethylamino and the diisopropylamino radicals.

Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to thecarbonyl group one of the abovementioned mono- or di-1-4C-alkylaminoradicals. Examples which may be mentioned are the N-methyl- theN,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and theN-isopropylaminocarbonyl radical.

Mono-or Di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to whichone of the abovementioned mono- or di-1-4C-alkylamino radicals isbonded. Examples which may be mentioned are the methylaminosulfonyl, thedimethylaminosulfonyl and the ethylaminosulfonyl radical.

An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino[C₃H₇C(O)NH-] and the acetylamino radical [CH₃C(O)NH-].

An 1-4C-Alkylsulfonylamino radical is, for example, thepropylsulfonylamino [C₃H₇S(O)₂NH-] and the methylsulfonylamino radical[CH₃S(O)₂NH-].

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are themethoxycarbonyl [CH₃O-C(O)-] and the ethoxycarbonyl [CH₃CH₂O-C(O)-]radicals.

Phenyl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals, which is substituted by the phenyl radical. Examples which maybe mentioned are the benzyloxy and the phenethoxy radical.

Phenyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the phenethyl and the benzyl radical.

Pyridyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by a pyridyl radical. Examples which maybe mentioned are the pyridylethyl and the pyridylmethyl radical.

N-oxide denotes the N-oxide on the pyridine which is substituted by OR4.

Compounds according to this invention which may be mentioned include forexample compounds of formula Ia

in which R1, R4 and R11 have the meanings given above and A suitablyincludes 3H-imidazo[[4,5-b]pyridin-2-yl,7-methyl-3H-imidazo[4,5-b]pyridin-2-yl,5,7-dimethyl-3H-imidazo[4,5-b]pyridin-2-yl,5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl,6-brom-3H-imidazo[4,5-b]pyridin-2-yl,7-methoxy-3H-imidazo[4,5-b]pyridin-2-yl,7-hydroxy-3H-imidazo[4,5-b]pyridin-2-yl,7-ethoxy-3H-imidazo[4,5-b]pyridin-2-yl,7-(2-methoxy-ethoxy)-imidazo[4,5-b]pyridin-2-yl,7-(1,1,1-trifluoroethoxy)-3H-imidazo[4,5-b]pyridin-2-yl,7-(phenylethoxy)-3H-imidazo[4,5-b]pyridin-2-yl,7-(phenylethyl)-3H-imidazo[4,5-b]pyridin-2-yl,7-(tolylethyl)-3H-imidazo[4,5-b]pyridin-2-yl,7-(pyrid-4-ylethyl)-3H-imidazo[4,5-b]pyridin-2-yl,7-(pyrid-2-ylethyl)-3H-imidazo[4,5-b]pyridin-2-yl,7-(pyrid-3-ylethyl)-3H-imidazo[4,5-b]pyridin-2-yl,7-(4-methoxypyrid-2-ylethyl)-3H-imidazo [4,5-b]pyridin-2-yl,6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl,6-n-butyl-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-methylphenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-nitro-3H-imidazo[4,5-b]pyridin-2-yl,6-(pyrid-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-cyanophenyl)-3H-imidazo [4,5-b]pyridin-2-yl,6-methyl-3H-imidazo[4,5-b]pyridin-2-yl,6-trifluoromethyl-3H-imidazo[4,5-b]pyridin-2-yl,6-iodo-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-aminophenyl)-3H-imidazo[4,5b]pyridin-2-yl,6-(4-dimethylaminophenyl)-3H-imidazo[4,5b]pyridin-2-yl,6-(4-hydroxyphenyl)-3H-imidazo[4,5b]pyridin-2-yl,6-(4-trifluoromethylphenyl)-3H-im idazo[4,5-b]pyridin-2-y I,6-(4-phenylsu lfonylaminophenyl)-3H-i midazo[4,5-b]pyridin-2-yl,6-(3,4dimethoxyphenyl)-3H-imidazo[4,5b]pyridin-2-yl,6-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(3,5-dichlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-benzyloxyphenyl)-3H-imidazo [4,5-b]pyridi n-2-yl,6-(4-benzyloxy-3-fluoro-phenyl)-3H-im idazo[4,5-b]pyridin-2-yl,6-(3-methyl-butyl)-3H-imidazo[4,5b]pyridin-2-yI,6-cyclohexylmethyl-3H-imidazo[4,5b] pyridin-2-yl,6-benzyl-3H-imidazo[4,5-b]pyridi n-2-yl,6-ethyl-3H-imidazo[4,5-b]pyridin-2-yl,6-isopropyl-3H-imidazo[4,5-b]pyridin-2-yl,6-n-pentyl-3H-imidazo[4,5-b]pyridin-2-yI,6-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(24luorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-bromophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(3-bromophenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(3-methylphenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-phenethyl-3H-imidazo[4,5-b]pyridin-2-yl, 6(3phenylpropyl)-3H-imidazo[4,5-b]pyridin-2-yl, 6(4-bromo-phenyl-methyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-acetamido-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl, 6(4-methoxycarbonyl-phenyl)-H-imidazo[4,5-b]pyridin-2-yl,6-(4-carboxy-phenyl)-3H-imidazo [4,5-b]pyridin-2-yl,6-methoxycarbonyl-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-dimethylamino-carbonyl-phenyl)3H-imidazo[4,5b]pyridin-2-yl,6-(4-dimethylaminosulphonyl-phenyl)-3H-imidazo [4,5-b]pyridin-2-yl,6-(4-diethylaminosulphonyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6-(4-methylamino-sulphonyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl,6(4-aminosulphonyl-phenyl)-3H-imidazo [4,5-b]pyridin-2-yl,6-(4-othylaminosulphonyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl or6-(3-luoro-4-dimethylaminosulphonyl-phenyl)-3H-imidazo[4,5b]pyridin-2-yl.

Suitable salts for compounds of formula I—depending on substitution—areall acid addition salts or all salts with bases. Particular mention maybe made of the pharmacologically tolerable inorganic and organic acidsand bases customarily used in pharmacy. Those suitable are, on the onehand, water-insoluble and, particularly, water-soluble acid additionsalts with acids such as, for example, hydrochloric acid, hydrobromicacid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citricacid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid,butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malicacid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonicacid, stearic acid, toluenesulphonic acid, methanesulphonic acid or3hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether a mono- or polybasic acid is concernedand depending on which salt is desired—in an equimolar quantitativeratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

A person skilled in the art knows on the base of his/her expertknowledge that the compounds according to this invention can exist, withregard to the fused imidazo ring, in different tautomeric forms such ase.g. in the 1-H form or, preferably, in the 3-H form, which is shown informula I. The invention includes all conceivable tautomers in pure formas well as in any mixing ratio. Particularly the present inventionincludes the pure 1-H- and, preferably, 3-H-tautomers as well as anymixtures thereof.

Compounds according to this invention worthy to be mentioned are thosecompounds of formula I in which

R1 is hydrogen or 1-4C-alkyl,

R2 is hydrogen,

R3 is hydrogen,

R4 is methyl,

R11 is 1-4C-alkyl,

and the salts, the N-oxides and the salts of the N-oxides of thesecompounds.

Compounds according to this invention more worthy to be mentioned arethose compounds of formula I in

which

either

R1 is hydrogen,

R2 is hydrogen,

R3 is hydrogen,

R4 is methyl, and

R11 is methyl or ethyl,

or

R1 is methyl,

R2 is hydrogen,

R3 is hydrogen,

R4 is methyl, and

R11 is methyl,

and the salts, the N-oxides and the salts of the N-oxides of thesecompounds.

The compounds of fornmula I according to the invention are, depending onthe meanings of R1 and R11, chiral compounds. The invention includes allconceivable enantiomers in pure form as well as in any mixing ratioincluding the racemate.

A special embodiment of the compounds of the present invention includethose compounds of formula I in which R4 is methyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R3 is hydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R4 is methyl and R3 ishydrogen.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is hydrogen and R11 ismethyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is hydrogen, R4 ismethyl and R11is methyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is hydrogen, R3 ishydrogen, R4 is methyl and R11 is methyl.

Another special embodiment of the compounds of the present inventioninclude those compounds of formula I in which the substituent R2 isbonded to the 6-position of the imidazopyridine ring system.

The substituents R2 and R3 of compounds of formula I according to thisinvention can be attached at any possible ring carbon atoms of thepyridine portion of the 3H-imidazo[4,5-b]pyridine ring system, whereby aspecial embodiment of the compounds of the present invention includethose compounds of formula I in which R2 is bonded to the 6-position ofthe imidazopyridine ring system and R3 is hydrogen.

The substituents R21 and R211 can be attached in the ortho, meta or paraposition with respect to the binding position in which the phenyl ringis bonded to the imidazopyridine ring system, whereby in a specialembodiment the substituent R21 is attached in the para position.

The compounds of formula I according to the invention can, for example,be prepared according to those synthesis routes specified and shownbelow or in a manner described by way of example in the followingexamples or analogously or similarly thereto.

Reaction scheme 1 below shows by way of example the preparation ofcompounds of formula I, in which R1 is hydrogen and R2, R3, R4 and R11have the meanings indicated above.

In a first reaction step diamino compounds of formula VI, in which R2and R3 have the meanings indicated above, are converted into3H-imidazo[4,5-b]pyridine derivatives in a manner known from theliterature or with analogous or similar use of processes known from theliterature. For example, said compounds of formula VI can be reactedwith carboxylic acids or carboxylic acid derivatives of formula V, inwhich R1 is hydrogen, R11 has the meanings indicated above, Y is asuitable leaving group, advantageously chlorine, and X is a cyano orcarboxyl radical, to give in a condensation reaction compounds offormula IV, in which R1 is hydrogen and R2, R3, R11 and Y have themeanings mentioned above. This condensation reaction can be carried outas known to one of ordinary skill in the art or as described by way ofexample in the following examples, for example, by using a suitablecondensing agent such as preferably polyphosphoric acid in a suitableinert solvent or, preferably, without further solvent using an excess ofcondensing agent, preferably at elevated temperature, in particular at130°-170° C.

Compounds of formula VI are commercially available or are known, e.g.from S.-X. Cai et al., J. Med. Chem. 1997, 40(22), 3679-3686, or can beobtained according to known procedures or analogously or similarlythereto.

Compounds of formula V are also commercially available or can beobtained in a known manner.

Alternatively, compounds of the formula IV, in which R1, R2, R3 and Yhave the meanings mentioned above and R11 is hydrogen, can be alsoobtained by art-known procedures according to literature (e.g. asdescribed in L. Bukowski et al., Pharmazie 1999, 54(9), 651-654 or G.Cleve et al. Liebigs Ann. Chem. 1971, 747, 158-171).

Compounds of formula IV, in which R1 is hydrogen and R2, R3, R11 and Yhave the meanings mentioned above, can be converted with certainphosphanes into corresponding phosphonium salts. Preferably, compoundsof formula IV are reacted with tributylphosphane or triphenylphosphaneto give corresponding compounds of formula III, in which R1 is hydrogenand R2, R3, R11 and Y have the meanings mentioned above and R is butylor phenyl. Said reaction can be carried out in a manner habitual per seor as described in the following examples in a suitable solvent such as,for example, acetonitrile or N,N-dimethylformamide or a mixture thereof,at elevated temperature, preferably at 90°-150° C., optionally in thepresence of an auxiliary such as tetrabutylammonium iodide.

Compounds of formula III, in which R1 is hydrogen and R2, R3, R11 and Yhave the meanings mentioned above and R is butyl or phenyl, are reactedwith compounds of formula VII, in which R4 has the meanings given above.Said reaction can be carried out in a manner as described in thefollowing examples or as known to the person skilled in the artaccording to a Wittig reaction. In the scope of this invention, saidWittig reaction is preferably carried out in a suitable solvent such as,for example, methanol or tetrahydrofurane, using a suitable base suchas, for example, sodium hydride or sodium methanolate, at roomtemperature or at elevated temperature, preferably at 50°-80° C. Withregard to the configuration of the exocyclic double bond obtained byWittig reaction, the outcome can be a Z- or E-configurated product or,in particular, a mixture thereof.

The reduction of the abovementioned exocyclic double bond following thedeprotection reaction leads to desired compounds of formula II, in whichR1 is hydrogen and R2, R3, R4 and R11 have the meanings given above.This reaction can be carried out as hydrogenation reaction according toprocedures known to the person skilled in the art or according to thefollowing examples in the presence of a suitable catalyst, such as, forexample, palladium on active carbon or platinum dioxide, in a suitablesolvent (e.g. in a lower alcohol, such as, for example, methanol). Ifnecessary, acid, such as trifluoracetic acid or acetic acid, can beadded to the reaction mixture.

Compounds of formula VII, in which R4 has the meanings mentioned above,can be obtained, for example, as described in Ashimori et al. Chem.Pharm. Bull. 1990, 38, 2446-2458 or analogously or similarly theretousing process steps known to the person skilled in the art.

Reaction scheme 2 below shows by way of example the preparation ofcompounds of formula I, in which R1 is hydrogen or, preferably,1-4C-alkyl and R2, R3, R4 and R11 have the meanings indicated above. Ina first reaction step compounds of formula VII, in which R4 has themeanings mentioned above, are converted into ester compounds—preferablythe methyl ester compounds—of formula IX, in which R1 is hydrogen or,preferably, 1-4C-alkyl and R4 and R11 have the meanings given above andR′ is suitably methyl, in a manner known from the literature (e.g.according to an aldol reaction) or with analogous or similar use ofprocesses known from the literature. For example, said compounds offormula VII can be reacted with suitable compounds of formula VII, inwhich R1 is hydrogen or, preferably, 1-4C-alkyl and R11 has the meaningsmentioned above and TMS represents trimethylsilyl, to obtain in an aldolreaction ester compounds—preferably the methyl ester compounds—of theformula IX, in which R1 is hydrogen or, preferably, 1-4C-alkyl and R4and R11 have the meanings given above. This aldol reaction is carriedout as described in the following examples or as known to one ofordinary skill in the art. With regard to the configuration of thecarbon atom to which the hydroxyl group is bounded, the outcome of saidaldol reaction can—depending on the reaction conditions—be a R- orS-configurated carbon atom or, in particular, a mixture thereof.

Said compounds of formula VIII are known and/or commercially availableor they can be prepared according to art-known procedures or similarlyor analogeously thereto.

In a second step the hydroxyl radical of ester compounds—preferably themethyl ester compounds—of formula IX, in which R1 is hydrogen or,preferably, 1-4C-alkyl and R4 and R11 have the meanings indicated above,is deoxygenated to give corresponding compounds of formula X. Saiddeoxygenation can be achieved in a manner familiar to the person skilledin the art or as described by way of example in the following examples.Advantageously, the hydroxyl radical is converted firstly into an easilyreducible functional group, which is then removed by a reductionreaction to obtain desired compounds of formula X. Thus, for example,the hydroxyl radical of said compounds of formula IX can be convertedinto the iodine radical in an art-known manner (e.g. by derivatizationof the hydroxyl radical with a suitable leaving group, preferably thetrifluoromethanesulfonyl group, and subsequent replacement of saidleaving group by an iodine nucleophile in a nucleophilic substitutionreaction). Thereafter, the iodine radical obtained can be reduced in amanner known to the person skilled in the art using, for example, asuitable hydrogen donor or a suitable hydrogen producing mixturecomprising, for example, a suitable metal, preferably zinc, to obtaindesired compounds of formula X. Most preferably, said deoxygenationreaction is carried out as described in the following examples employingin the final step sodium iodide and zinc in a one-pot procedure in asuitable solvent, such as dimethoxyethane, at elevated temperature.

In a third step ester compounds—preferably the methyl ester compounds—offormula X, in which R1 is hydrogen or, preferably, 1-4C-alkyl and R4 andR11 have the meanings indicated above, are saponificated in a mannerdescribed in the following examples or as known to the person skilled inthe art to give corresponding compounds of formula XI.

In the next step compounds of formula XII, in which R1 is hydrogen or,preferably, 1-4C-alkyl and R2, R3, R4 and R11 have the meaningsindicated above, are prepared from compounds of formula XI, in which R1is hydrogen or, preferably, 1-4C-alkyl and R4 and R11 have theabovementioned meanings, and compounds of formula VI, in which R2 and R3have the abovementioned meanings, in a manner habitual per se to theperson skilled in the art, for example by reaction with amide bondlinking reagents known to the person skilled in the art. Exemplary amidebond linking reagents known to the person skilled in the art which maybe mentioned are, for example, carbodiimides, azodicarboxylic acidderivatives, uronium salts, N,N′-carbonyldiimidazole or, preferably,phosphonium salts such as, for example,benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate.

In the final step compounds of formula XII, in which R1 is hydrogen or,preferably, 1-4C-alkyl and R2, R3, R4 and R11 have the meanings givenabove, are converted into compounds of formula I, in which R1 ishydrogen or, preferably, 1-4C-alkyl and R2, R3, R4 and R11 have themeanings given above, by cyclocondensation reaction. Saidcyclocondensation reaction is carried out in a manner known per se tothe person skilled in the art or as described by way of example in thefollowing examples, according to Bischler-Napieralski (e.g. as describedin J. Chem. Soc., 1956, 4280-4282) in the presence of a suitablecondensing agent, such as, for example, polyphosphoric acid, phosphoruspentachloride, phosphorus pentoxide or phosphorus oxychlonde, in asuitable inert solvent, e.g. in a chlorinated hydrocarbon such aschloroform, or in a cyclic hydrocarbon such as toluene or xylene, oranother inert solvent such as isopropyl acetate or acetonitrile, orwithout further solvent using an excess of condensing agent, at reducedtemperature, or at room temperature, or at elevated temperature or atthe boiling temperature of the solvent or condensing agent used.

Alternatively, compounds of formula XI can be also directly cyclizedwith compounds of formula VI under suitable conditions (e.g. inpolyphosphoric acid at elevated temperature) to give the desiredcompounds of formula I.

Compounds of formula I, in which R2 is phenyl or R21- and/orR211-substituted phenyl, can be prepared, for example, as described byway of example in the following examples or according to processes knownfrom literature or analogously or similarly thereto, for examplestarting from the corresponding compounds. of formula I, in which R2 orR3 is preferably iodine or bromine, e.g. according to known metalcatalyzed CC-coupling reactions, such as e.g. the Suzuki reaction is.This Suzuki reaction can be carried out as known to the person skilledin the art using, for example, appropriate boronic acids or boronic acidderivatives and suitable metal catalysts, preferably transition metalcatalysts (such as, for example, palladium catalysts), optionally, inthe presence of an inorganic lithium salt, preferably lithium chloride.Said boronic acids or boronic acid derivatives can be prepared accordingto art-known manners, e.g. from R21- and/or R211-substituted phenylhaides or triflates using e.g. bis-(pinacolato)-diboron.

Compounds of formula I, in which R2 is 1-4C-alkoxycarbonyl, can beobtained, for example, in a manner known to the person skilled in theart according, for example, a metal catalyzed (e.g. a transition metalcatalyzed, preferably palladium catalyzed) carbonylation reaction of thecorresponding compounds of formula I, in which R2 or R3 is preferablyiodine or bromine, in the presence of a suitable alcohol.

Compounds of formula I, in which R21 is 1-4C-alkylcarbonylamino orphenylsulfonylamino, can be prepared, for example, according toprocesses known from literature or analogously or similarly theretostarting from the corresponding compounds of formula I, in which R21 isamino, e.g. by acylation or sulfonylation reaction habitual per se tothe skilled person.

The compounds according to the invention can be converted, optionally,into their N-oxides, for example with the aid of hydrogen peroxide inmethanol or with the aid of m-chloroperoxybenzoic acid indichloromethane. The person skilled in the art is familiar on the basisof his/her expert knowledge with the reaction conditions which arespecifically necessary for carrying out the N-oxidation.

It is known to the person skilled in the art that if there are a numberof reactive centers on a starting or intermediate compound it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T.Greene and P. Wuts, “Protective Groups in Organic Synthesis” (John Wiley& Sons, Inc. 1999, 3^(rd) Ed.) or in P. Kocienski, “Protecting Groups(Thieme Foundations Organic Chemistry Series N Group” (Thieme MedicalPublishers, 2000).

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art, for example, in the manner which is describedby way of example in the following examples.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds according to this invention. Allthese other possible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicite, implicite or inherent disclosure) of the presentinvention without departing from the spirit and scope of this invention.

The following examples illustrate the invention in greater detail,without restricting It. As well, further compounds according to thepresent invention, of which the preparation is explicitly not described,can be prepared in an analogous way or in a way which is known by aperson skilled in the art using customary preparation methods andprocess techniques.

In the examples, m.p. stands for melting point, h for hours, d for days,min for minutes, TLC for thin layer chromatography, Rf for retentionfactor, MS for mass spectrum, M for molecular ion, other abbreviationshave their meanings customary per se for the skilled person.

The compounds, which are mentioned in the examples as well as theirsalts are preferred compounds of the invention.

EXAMPLES

FINAL PRODUCTS

1.(R,S)-2-[3-(4-Methoxypyridin-2-yl)prop-2-yl]-3H-imidazo[4,5-b]pyridinehydrochloride

A solution of 0.59 g of 4-methoxypyridine-2-carbaldehyde (Ashimori etal., Chem. Pharm. Bull. 38, 2446-2458 (1990)) in 19 ml of methanol istreated with 1.9 g of{1-(3H-imidazo[4,5-b]pyridin-2-yl)-ethyl}-triphenyl-phosphonium chloride(compound A1). 3.3 ml of a solution of sodium methanolate in methanol(1.3 M) are added dropwise at 50° C. The reaction mixture is stirred at50° C. for 4 h and evaporated to dryness. The resulting residue ischomatographed on silica gel using dichloromethane/methanol 20:1 to give1.75 g of a colorless, amorpheous solid, which is dissolved in 190 ml ofmethanol. 1.5 ml of glacial acetic acid and 388 mg of palladium onactive carbon (10% Pd) are added and the suspension is stirred at roomtemperature for 2.5 d under hydrogen atmosphere. Then the catalyst isfiltered off and the reaction mixture is concentrated to dryness. Afterchromatographical purification of the residue on silica gel(dichoromethane/methanol 25:1) and evaporation of the eluents, 837 mg ofan oil are obtained, which is dissolved in 160 ml of dichloromethane. 2ml of an ethereal hydrochloric acid solution (2.0 M) are added to thesolution under ice-cooling. After lyophillization from dioxane, 0.951 gof the title compound are obtained as a colorless lyophilisate. M.p.61°-64° C. MS: 269.1 (MH+). TLC: Rf=0.44 (dichloromethane/methanol10:1).

2. (R.S)-2-[4-(4-Methoxypyridin-2-yl)but-2-yl]-3H-imidazo[4,5-b]pyridine

A solution of 7.2 g oftributyl-{1-(3H-imidazo[4,5-b]pyridin-2-yl)-propyl}-phosphonium chloride(compound A2) in tetrahydrofurane is added to a suspension of 720 mg ofsodium hydride (60% strength suspension in paraffin) in 180 ml oftetrahydrofurane. After 15 min stirring, a solution of 0.500 g of4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull.38, 2446-2458 (1990)) in tetrahydrofurane is added dropwise and thereaction mixture is heated at 80° C. for 6 h. The mixture is thenevaporated to dryness and the resulting residue chomatographed on silicagel using dichloromethane/methanol 20:1 to give 3.58 g of a colorless,amorpheous solid, which is dissolved as obtained in 200 ml of methanol.2.9 ml of trifluoracetic acid and 788 mg of palladium on active carbon(10% Pd) are added and the suspension is stirred at room temperature for2.5 d under hydrogen atmosphere. Then the catalyst is filtered off andthe reaction mixture is concentrated to dryness. After chromatographicalpurification of the residue on silica gel (dichoromethane/methanol 10:1to 5:1) and evaporation of the eluents, 1.4 g of the title compound areobtained as an oil. MS: 283.1 (MH+). TLC: Rf=0.48(dichloromethane/methanol 10:1).

3.2-[2-(4-Methoxypyridin-2-yl)-1,1-dimethyl-ethyl]-3-imidazo[4,5-b]pyridine

A solution of 3.56 g of 3-(4-methoxypyridin-2-yl)-2,2-dimethyl-propionicacid (compound A3), 2.05 g of 2,3-diaminopyridine and 12.42 g ofbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphatein 178 ml of pyridine is treated dropwise with 3.5 ml ofN,N′-diisopropylethylamine. After complete addition, the reactionmixture is stirred at 40° C. for 22 h. Then the reaction mixture isconcentrated to dryness and the residue purified by chromatography onsilica gel (dichloromethane/methanol 10:1) to give 4.19 g of the amideintermediate, which is suspended as obtained in 51.5 ml ofphosphoroxychloride. The reaction mixture is refluxed for 19 h,evaporated to dryness, the resulting residue is dissolved in 190 ml ofwater, with the aid of 2 M aqueous sodium hydroxide solution the pH isadjusted to pH 6 and the mixture is extracted four times with each 100ml of dichloromethane. The organic layers are collected, washed with 100ml of water and 100 ml of brine, dried using sodium sulfate andconcentrated. After chromatographical purification of the residue onsilica gel (dichoromethane/methanol 20:1) and evaporation of theeluents, 0.624 of the title compound are obtained as colorless, waxysolid. M.p. 149°-15120 C. MS: 283.3 (MH+). TLC: Rf=0.27(dichloromethane/methanol 10:1).

STARTING MATERIALS A1.{1-(3H-Imidazo[4,5-b]pyridin-2-yl)-ethyl{-triphenyl-phosphonium chloride

8.66 g of 2-(1-chloroethyl)-3H-imidazo[4,5-b]pyridine (compound B1) aresuspended in 40 ml of N,N-dimethylformamide and 120 ml of acetonitrile.12.6 g of triphenylphosphine are added and the mixture is heated to 150°C. for 17 h. The mixture is concentrated to dryness and the crudeproduct purified by chromatography on silica gel (eluent:dichloromethane/methanol 20:1) to afford 4.16 g of the title compound asan oil. MS: 408.0 (M+).

A2. Tributyl-{1-(3H-imidazo[4.5-b]pyridin-2-yl)-propyl}-phosphoniumchloride

8.66 g of 2-(1-chloropropyl)-3H-imidazo[4,5-b]pyridine (compound B2) aresuspended in 18 ml of N,N-dimethylformamide and 61 ml of acetonitrile.6.3 ml of triphenylphosphine are added at 40° C. and the mixture isheated to 90° C. for 16 h. The mixture is concentrated to dryness togive 11.9 g of the title compound as an oil. MS: 362.2 (M+).

A3. 3-(4-Methoxynyridin-2-yl)-2,2-dimethyl-propionic acid

A solution of 1.0 g of 3-(4-methoxypyridin-2-yl)-2,2-dimethyl-propionicacid methyl ester (compound B3) in 52 ml of dioxane is treated dropwisewith 12.1 ml of an aqueous solution of lithium hydroxide (290 mg oflithium hydroxide in 12.1 ml of water). After stirring at 50° C. for 3.5h, the pH is adjusted to pH 6 by addition of aqueous hydrochloric acid(1 M). The solvents are removed in vacuo and the remaining residue ispurified by chromatography on silica gel (dichloromethane/methanol 15:1)to obtain 0.864 g of the title compound as colorless, amorpheous solid.M.p. 150°- 151° C. MS: 210.2 (MH+). TLC: Rf=0.27(dichloromethane/methanol 10:1).

B1. 2-(1-Chloroethyl)-3H-imidazo[4,5-b]pyridine

5.2 g of 2,3-diaminopyridine in 209 g of polyphosphoric acid are heatedat 120° C. for 0.5 h. The solution is cooled to 80° C. and 4.6 ml of2-chloropropionitrile are added. Thereafter, the reaction mixture isheated to 180° C. for 2.5 h. After cooling, the polyphosphoric acid ishydrolyzed with water, the mixture is filtered using charcoal and celiteand the pH value of the filtrate is adjusted to pH 4 using 9 M aqueoussodium hydroxide solution. The mixture is extracted twice each with 250ml of ethyl acetate, the combined organic phases are dried using sodiumsulfate, concentrated and lyophilized from ethanol/water to give 3.56 gof the title compound as a light brown, amorpheous solid. M.p. 132° C.TLC: Rf=0.60 (dichloromethane/methanol 8:1).

B2. 2-(1-Chloropropyl)-3H-imidazo[4,5-b]pyridine

5.0 g of 2,3-diaminopyridine in 200 g of polyphosphoric acid are heatedat 120° C. for 0.5 h. The solution is cooled to 80° C. and 5.7 ml of2-chlorobutyric acid are added. Thereafter, the reaction mixture isheated to 130° C. for 22 h. After cooling, the polyphosphoric acid ishydrolysed with water, the mixture is filtered using charcoal and celiteand the pH value of the filtrate is adjusted to pH 4 using 9 M aqueoussodium hydroxide solution. The mixture is extracted three times eachwith 200 ml of ethyl acetate, the combined organic phases are driedusing sodium sulfate, concentrated and the residue is purified bychromatography on silica gel (eluent: toluene/ethyl acetate 1:1) to give5.19 g of the title compound as a colorless, amorpheous solid. M.p. 137°C. TLC: Rf=0.50 (dichloromethane/methanol 10:1).

B3. 3-(4-Methoxypyridin-2-yl)-2,2-dimethyl-propionic acid methyl ester

3.0 g of 3-hydroxy-3-(4-methoxypyridin-2-yl)-2,2-dimethyl-propionic acidmethyl ester (compound C3), 0.153 g of 4-dimethylaminopyridine and 2.58ml of N,N′-diisopropylethylamine are dissolved in 80 ml ofdichloromethane. Trifluoromethanesulfonic acid anhydride is addeddropwise under ice-cooling. The cooling bath is removed and the mixtureis stirred at room temperature for 2.5 h. After evaporation in vacuo,the remaining residue is dissolved as obtained in 100 ml of1,2-dimethoxyethane. 9.37 g of sodium iodide and 16.3 g of activatedzinc are added and the mixture is stirred at 100° C. for 1.5 h. Thesolids are filtered off, the filtrate is diluted with 800 ml ofdichloromethane and extracted several times with halfsaturated aqueoussodium chloride solution. The organic layer is dried using sodiumsulfate and concentrated. The residue is purified by chromatography onsilica gel (toluene/ethyl acetate 2:1) to afford 1.6 g of the titlecompound as an oil. MS: 224.2 (MH+). TLC: Rf=0.26 (toluene/acetone 2:1).

C3. 3-Hydroxy-3-(4-methoxypyridin-2-yl)-2,2-dimethyl-propionic acidmethyl ester

A solution of 0.58 g of 4-methoxypyridine-2-carbaldehyde (Ashimori etal., Chem. Pharm. Bull. 38, 2446-2458 (1990)) and 21 mg of scandiumtrifluoromethanesulfonate in 14 ml of dichloromethane is treateddropwise with 0.9 ml of 1-methoxy-2-methyl-1-trimethylsilyloxypropaneunder ice-cooling. After 10 min the cooling bath is removed and themixture is stirred for 18 h. Thereafter, 12 ml of methanol and 12 ml ofaqueous hydrochloric acid (3 M) are added and stirring is continued forfurther 14 h. The solvents are removed in vacuo, the residue isdissolved in dichloromethane and washed with saturated aqueous sodiumhydrogencarbonate solution. The organic layer is dried using sodiumsulfate and concentrated to give 0.845 g of the title compound as acolorless oil. MS: 240.0 (MH+). TLC: Rf=0.46 (toluene/acetone 2:1).

COMMERCIAL APPLICABILITY

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. They are selectiveinhibitors of the enzyme inducible nitric oxide synthase. Nitric oxidesynthases (NO-syntases, NOSs) are enzymes that generate NO andcitrulline from the amino acid arginine. In certain pathophysiologicalsituations such as arginine depletion or tetrahydrobiopterin depletionthe generation of O₂ from NO-synthases instead or together with NO hasbeen reported. NO is long known as a signalling molecule in most livingorganisms including mammals and humans. The most prominent action of NOis it's smooth muscle relaxing activity, which is caused on themolecular level by the activation of soluble guanylate cyclase. In thelast years a lot of other enzymes have been shown to be regulated by NOor reaction products of NO.

There exist three isoforms of NO-synthases which fall into two classesand differ in their physiologic functions and molecular properties. Thefirst class, known as constitutive NO-synthases, comprises of theendothelial NO-synthase and the neuronal NO-synthase. Both isoenzymesare expressed constitutively in various cell types, but are mostprominent in endothelial cells of blood vessel walls (therefore calledendothelial NO-synthase, eNOS or NOS-III) and in neuronal cells(therefore called neuronal NO-synthase, nNOS or NOS-I). Activation ofthese two enzymes is dependent on Ca²⁺/Calmodulin which is generated bytransient increases of the intracellular free Ca²⁺concentration.Activation of constitutive isoforms leads to transient bursts of nitricoxide resulting in nanomolar cellular or tissue NO concentrations. Theendothelial isoform is involved in the physiologic regulation of bloodpressure. NO generated by the neuronal isoform seems to haveneurotransmitter function and the neuronal isoform is among otherregulatory processes involved in memory function (long termpotentiation).

In contrast to the constitutive isoforms the activation of inducibleNO-synthase (iNOS, NOS-II), the sole member of the second class, isperformed by transcriptional activation of the iNOS-promoter.Proinflammatory stimuli lead to transcription of the gene for inducibleNO-synthase, which is catalytically active without increases in theintracellular Ca²⁺-concentration. Due to the long half live of theinducible NO-synthase and the unregulated activity of the enzyme, highmicromolar concentrations of NO are generated over longer time periods.These high NO-concentrations alone or in cooperation with other reactiveradicals such as O₂ are cytotoxic. Therefore, in situations of microbialinfections, iNOS is involved in cell killing by macrophages and otherimmune cells during early nonspecific immune responses.

There are a number of pathophysiological situations which among othersare characterized by the high expression of inducible NO-synthase andconcomitant high NO or O₂ concentrations. It has been shown that thesehigh NO concentrations alone or in combination with other radicalspecies lead to tissue and organ damage and are causally involved inthese pathophysiologies. As inflammation is characterized by theexpression of proinflammatory enzymes, including inducible NO-synthase,acute and chronical inflammatory processes are promising diseases forthe therapeutic application of selective inhibitors of inducibleNO-synthase. Other pathophysiologies with high NO-production frominducible NO-synthase are several forms of shock (septic, hemorrhagicand cytokine-induced).

It is clear that nonselective NO-synthase inhibitors will lead tocardiovascular and neuronal side effects due to concomitant inhibitionof constitutive NO-synthase isoforms.

It has been shown in in-vivo animal models of septic shock thatreduction of circulating plasma NO-levels by NO-scavenger or inhibitionof inducible NO-synthase restores systemic blood pressure, reduces organdamage and increases survival (deAngelo Exp. Opin. Pharmacother. 19-29,1999; Redl et al. Shock 8, Suppl. 51, 1997; Strand et al. Crit.Care Med.26, 1490-1499, 1998). It has also been shown that increased NOproduction during septic shock contributes to cardiac depression andmyocardial dysfunction (Sun et al. J. Mol.Cell Cardiol. 30, 989-997,1998). Furthermore there are also reports showing reduced infarct sizeafter occlusion of the left anterior coronary artery in the presence ofNO-synthase inhibitors (Wang et al. Am. J. Hyperttens. 12, 174-182,1999). Considerable inducible NO-synthase activity is found in humancardiomyopathy and myocarditis, supporting the hypothesis that NOaccounts at least in part for the dilatation and impaired contractilityin these pathophysiologies (de Belder et al. Br. Heart. J. 4, 426-430,1995).

In animal models of acute or chronic inflammation, blockade of inducibleNO-synthase by isoform-selective or nonselective inhibitors or geneticknock out improves therapeutic outcome. It is reported that experimentalarthritis (Connor et al. Eur. J. Pharmacol. 273, 15-24, 1995) andosteoarthritis (Pelletier et al. Arthritis & Rheum. 41, 1275-1286,1998), experimental inflammations of the gastro-intestinal tract(Zingarelli et al. Gut 45, 199-209, 1999), experimentalglomerulonephritis (Narita et al. Lab. Invest. 72, 17-24, 1995),experimental diabetes (Corbett et al. PNAS 90, 8992-8995, 1993),LPS-induced experimental lung injury is reduced by inhibition ofinducible NO-synthase or in iNOS-knock out mice (Kristof et al. Am. J.Crit. Care. Med. 158,1883-1889, 1998). A pathophysiological role ofinducible NO-synthase derived NO or O₂ is also discussed in chronicinflammatory diseases such as asthma, bronchitis and COPD.

Furthermore, in models of neurodegenerative diseases of the CNS such asMPTP-induced parkinsonism, amyloid peptide induced Alzheimer's disease(Ishii et al., FASEB J. 14, 1485-1489, 2000), malonate inducedHuntington's disease (Connop et al. Neuropharmacol. 35, 459-465, 1996),experimental menengitis (Korytko & Boje Neuropharmacol. 35, 231-237,1996) and experimental encephalitis (Parkinson et al. J. Mol. Med. 75,174-186, 1997) a causal participation of NO and inducible NO-synthasehas been shown.

Increased iNOS expression has been found in the brains of AIDS victimsand it is reasonable to assume a role of iNOS in AIDS related dementia(Bagasra et al. J. Neurovirol. 3 153-167, 1997).

Other studies Implicated nitric oxide as a potential mediator ofmicroglia dependent primary demyelination, a hallmark of multiplesklerosis (Parkinson et al. J. Mol. Med. 75, 174-186,1997).

An inflammatory reaction with concomitant expression of inducibleNO-synthase also takes place during cerebral ischemia and reperfusion(ladecola et al. Stroke 27, 1373-1380, 1996). Resulting NO together withO₂ from infiltrating neutrophils is thought to be responsible forcellular and organ damage. Also, in models of traumatic brain injury(Mesenge et al. J. Neurotrauma 13, 209-214,1996; Wada et al.Neurosurgery 43, 1427-1436, 1998) NO-synthase inhibitors have been showto posses protective properties. A regulatory role for inducibleNO-synthase has been reported in various tumor cell lines (Tozer &Everett Clin Oncol. 9. 357-264,1997).

On account of their inducible NO-synthase-inhibiting properties, thecompounds according to the invention can be employed in human andveterinary medicine and therapeutics, where an excess of NO or O₂ due toincreases in the activity of inducible NO-synthase is involved. They canbe used without limitation for the treatment and prophylaxis of thefollowing diseases:

Acute inflammatory diseases: Septic shock, sepsis, SIRS, hemorrhagicshock, shock states induced by cytokine therapy (IL-2, TNF), organtransplantation and transplant rejection, head trauma, acute lunginjury, ARDS, inflammatory skin conditions such as sunburn, inflammatoryeye conditions such as uveitis, glaucoma and conjunctivitis.

Chronic inflammatory diseases of peripheral organs and the CNS:gastrointestinal inflammatory diseases such as Crohn's disease,inflammatory bowel disease, ulcerative colitis, lung inflammatorydiseases such as asthma and COPD, arthritic disorders such as rheumatoidarthritis, osteoarthritis and gouty arthritis, heart disorders such ascardiomyopathy and myocarditis, artherosklerosis, neurogenicinflammation, skin diseases such as psoriasis, dermatitis and eczema,diabetes, glomerulonephritis; dementias such as dementias of theAlzheimer's type, vascular dementia, dementia due to a general medicalcondition, such as AIDS-, Parkinson's disease, Huntington's induceddementias, ALS, multiple sklerosis; necrotizing vasculitides such aspolyarteritis nodosa, serum sickness, Wegener's granulomatosis,Kawasaki's syndrom; headaches such as migraine, chronic tensionheadaches, cluster and vascular headaches, post-traumatic stressdisorders; pain disorders such as neuropathic pain; myocardial andcerebral ischemia/reperfusion injury.

The compounds may also be useful in the treatment of cancers thatexpress nitric oxide synthase.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the abovementionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions having aniNOS inhibitory activity.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

The invention moreover relates to pharmaceutical compositions accordingto this invention having an iNOS inhibitory activity.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, caplets,suppositories, patches (e.g. as TTS), emulsions, suspensions, gels orsolutions, the active compound content advantageously being between 0.1and 95% and where, by the appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or an enteric form) exactly sufted to the active compound and/or tothe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdernal and rectal delivery. Oral and intravenous deliveryare preferred.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantagously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further processed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for iNOS inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.1 and 10 mg per day. The customary dose in the case of systemictherapy (p.o.) is between 0.3 and 30 mg/kg per day, (i. v.) is between0.3 and 30 mg/kg/h.

BIOLOGICAL INVESTIGATIONS

Measurement of Inducible NO-synthase Activity

The assay is performed in 96-well microtiter F-plates (Greiner,Frickenhausen, FRG) in a total volume of 100 μl in the presence of 100nM calmodulin, 226 μM CaCl₂, 477 μM MgCl₂, 5 μMflavin-adenine-dinucleotide (FAD), 5 μM flavin mononucleotide (FMN), 0.1mM NADPH, 7 mM glutathione, 10 μM BH4 and 100 mM HEPES pH 7.2. Arginineconcentrations are 0.1 μM for enzyme inhibition experiments. 150000 dpmof [³H]arginine are added to the assay mixture. Enzyme reaction isstarted by the addition of 4 μg of a crude cytosolic fraction containinghuman inducible NO-synthase and the reaction mixture is incubated for 45to 60 min at 37° C. Enzyme reaction is stopped by adding 10 μl of 2MMESbuffer pH 5,0. 50 μp of the incubation mixture are transferred into aMADP N65 filtration microtiter plate (Millipore, Eschborn, FRG)containing already 50 μl of AG-50W-X8 cation exchange resin (Biorad,München, FRG). The resin in the Na loaded form is pre-equilibrated inwater and 70 μp (corresponding to 50 μl dry beads) are pipetted underheavy stirring with a 8 channel pipette into the filtration plate. Afterpipetting 50 μl of the enzyme reaction mixture onto the filtrationplates, the plates are placed on a filtration manifold (Porvair,Shepperton, UK) and the flow through is collected in Pico scintillationplates (Packard, Meriden, Conn.). The resin in the filtration plates iswashed with 75 μl of water (1×50 μl and 1×25 μl) which is also collectedin the same plate as the sample. The total flow through of 125 μl ismixed with 175 μl of Microscint-40 scintillation cocktail (Packard) andthe scintillation plate is sealed with TopSeal P-foil (Packard).Scintillation plates are counted in a szintillation counter.

For the measurement of inducible NO-synthaseinhibiting potencies ofcompounds increasing concentrations of inhibitors were included into theincubation mixture. IC₅₀-values were calculated from the percentinhibition at given concentrations by nonlinear least square fitting.

Representative inhibitory values determined for the compounds accordingto the invention follow from the following table A, in which thecompound numbers correspond to the example numbers. TABLE A Inhibitionof iNOS activity [measured as −logIC₅₀ (mol/l)] compound −logIC₅₀ 1 7.15

1. Compounds of formula I

in which R1 is hydrogen or 1-4C-alkyl, R2 is hydrogen, halogen,hydroxyl, nitro, amino, 1-7C-alkyl, trifluoromethyl, 3-7C-cycloalkyl,3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, completely or predominantlyfluorine-substituted 1-4C-alkoxy, 1-4C-alkoxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxycarbonyl, mono- or di-1 -4C-alkylaminocarbonyl,mono- or di-1-1-4C-alkylaminosulfonyl, 1-4C-alkylcarbonylamino,1-4C-alkylsulfonylamino,3 phenyl, R21- and/or R211-substituted phenyl,phenyl-1-4C-alkyl, phenyl-1-4C-alkyl wherein the phenyl moiety issubstituted by R22, phenyl-1-4C-alkoxy, pyridyl, pyridyl substituted byR23, pyridyl-1-4C-alkyl, pyridyl-1-4C-alkyl wherein the pyridyl moietyis substituted by R24, in which R21 is cyano, halogen, carboxyl,1-4C-alkyl, 1-4C-alkoxy, ami nocarbonyl, mono- ordi-1-4C-alkykaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl,amino, mono- or di-1-4C-alkylamino, trifluoromethyl, hydroxyl,phenylsulfonylamino or phenyl-1-4C-alkoxy, R211 is halogen or1-4C-alkoxy, R22 is halogen, 1-4C-alkyl or 1-4C-alkoxy, R23 is halogen,1-4C-alkyl or 1-4C-alkoxy, R24 is halogen, 1-4C-alkyl or 1-4C-alkoxy, R3is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R4 is 1-4C-alkyl, R11is 1-4C-alkyl, and the salts, the N-oxides and the salts of the N-oxidesof these compounds.
 2. Compounds according to claim 1 in which R1 ishydrogen or 1-4C-alkyl, R2 is hydrogen, R3 is hydrogen, R4 is methyl,R11 is 1-4C-alkyl, and the salts, the N-oxides and the salts of theNoxides of these compounds.
 3. Compounds according to claim 1 in whicheither R₁ is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is methyl, andR11 is methyl or ethyl, or R₁ is methyl, R2 is hydrogen, R3 is hydrogen,R4 is methyl, and R11 is methyl, and the salts, the N-oxides and thesalts of the N-oxides of these compounds.
 4. Compounds of formula Iaccording to claim 1 in which R4 is methyl, and the salts, the N-oxidesand the salts of the N-oxides of these compounds.
 5. Compounds offormula I according to claim 1 in which R1 is hydrogen, R4 is methyl andR11 is methyl, and the salts, the N-oxides and the salts of the N-oxidesof these compounds.
 6. Compounds of formula I according to claim 1 foruse in therapy, e.g. for the treatment of diseases.
 7. Pharmaceuticalcompositions containing one or more compounds of formula I according toclaim 1 together with the usual pharmaceutical auxiliaries and/orexcipients.
 8. Use of compounds of formula I according to claim 1 forthe production of pharmaceutical compositions for the treatment of acuteinflammatory diseases.
 9. Use of compounds of formula I according to oneof the claims 1 for the production of pharmaceutical compositions forthe treatment of chronic inflammatory diseases of peripheral organs andthe CNS.
 10. A method for treating illnesses in a patient comprisingadministering to said patient a therapeutically effective amount of acompound of formula I according to claim
 1. 11. A method for treatingacute inflammatory diseases in a patient comprising administering tosaid patient a therapeutically effective amount of a compound of formulaI according to claim 1.